The herpesviruses are important human pathogens, especially problematic for those afflicted with cancer and congenital or acquired immunodeficiency disease. The parameters of resistance and of control of recurrent infections are poorly understood. Evidence from animal and human studies indicate that cell-mediated immunity plays an important role in resistance to herpesvirus infections. Analysis of the various aspects of cell-mediated immunity which might play a role in host's defense against herpesvirus infections is difficult in the human patient because of the uncontrollable factors associated with activation of latent disease. I have recently discovered and developed a model of herpesvirus infections in the mouse which should allow the dissection of the mechanisms required for resistance. Genetically resistant and susceptible mouse strains have been identified and inoculation of backcross and F2 populations indicate that 2 independently segregating genes are required for resistance. Although genes within the H-2 of the mouse do not appear to play a role in natural resistance, experimental results indicate that resistance is immunologically mediated. A striking similarity between resistance of HSV-1 is governed by genes closely linked to the genes governing allogeneic marrow graft resistance and whether resistance to HSV-1 is also mediated by the "M" cell. In addition, lymphocyte-macrophage interactions leading to resistance will be investigated.